Animals such as mammals (including humans) are often susceptible to parasite infections and infestations. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Production animals, such as cows, pigs, sheep and goats, can be infected with one or more trematodes. Of particular concern here is Fasciola hepatica (i.e., liver fluke or F. hepatica).
Liver flukes are a particular problem because they adversely affect the health of the animal or human and can inflict significant economic loss in a domestic livestock population. It is estimated that F. hepatica poses a risk to at least 250 million sheep and 350 million cattle worldwide. Moreover, domestic animals other than sheep and cows may serve as intermediate hosts. Liver flukes can cause liver condemnation, secondary infections, reduced milk and meat production, abortion and fertility problems.
Several types of control measures for liver flukes have been introduced over the past century. First, halogenated hydrocarbons (e.g., CCl4; carbon tetrachloride) were introduced for ruminants in the 1920s. Halogenated hydrocarbons had limited success and are no longer used primarily because of their adverse effects and variable efficacy. Second, halogenated phenols were administered in the late 1950s (e.g., hexachlorophene and bithionol sulfoxide) followed by the similar halogenated salicylanilides (e.g., oxyclozanide, bromoxanide). Fourth, benzimidazole carbamates (e.g., albendazole, luxabendazole) were found to have a broad anthelmintic spectrum against nematodes and mature F. hepatica. Another benzimidazole—the chlorinated methylthiobenzimidazole derivative triclabendazole—has a high success rate against F. hepatica. Fifth, bisanilino compounds introduced in the 1960s were intolerable due to toxic side effects. Finally, benzene sulfonamides (e.g., clorsulon) were studied in the 1970s. Extensively modified examples of this class demonstrate high efficacy on both mature and immature F. hepatica. Of these six classes of anthelmintics the benzimidazole class is perhaps the most widely used for its high efficacy.
Indeed, triclabendazole is the current drug of choice against mature and immature liver flukes. Not surprisingly, however, reports of parasite resistance are increasing. For example, Mottier et al., report that a population of resistant F. hepatica (Sligo) may use an altered influx/efflux mechanism to selectively decrease the amount of triclabendazole and triclabendazole sulfoxide but not albendazole. See Mottier et al., J. Parasitol., 92(6), 2006, pp. 1355-1360. McConville et al., report that juvenile triclabendazole-resistant F. hepatica are somewhat susceptible to compound alpha (i.e., 5-chloro-2-methylthio-6-(1-naphthyloxy)-1H-benzimidazole) via a tubulin-independent mechanism. See McConville et al., Parasitol. Res., (2007) 100:365-377. Further, Keiser et al., report the testing of artemether and OZ78 in triclabendazole-resistant F. hepatica, although at high concentrations. For a short review of triclabendazole resistance see Brennan et al., Experimental and Molecular Pathology, 82, (2007) pp. 104-109.
There is, however, little in the literature disclosing indoles as a treatment for trematodes. Derquantel is in a class known as spiroindoles and is paired with a macrocyclic lactone for greater efficacy against sheep nematodes (e.g., gastrointestinal and respiratory parasites) but no data is currently available as to the effectiveness of derquantel against trematodes.
Other indole compounds have demonstrated an effect on F. hepatica. Indolamines such as serotonin (5-hydroxytryptamine) have a stimulant effect on the rhythmical activity of the trematode that is antagonized by other compounds also having an indole structure (e.g., bromolysergic acid diethylamide and yohimbine; Mansour, Brit. J. Pharmacol. (1957), 12, 406.)
WO 2007/051619 discloses aryl indole derivatives as pesticides. The '619 application speculates that the aryl indole derivatives that it discloses would be effective against trematodes such as F. hepatica but offers evidence only against the dog tick, the cat flea, and certain gastrointestinal nematodes.
WO 2012/125662 discloses indole derivatives useful as ccr2 (i.e., chemokine receptor type 2) antagonists. The '662 application further speculates that the compounds of its disclosure may be effective against trematodes but offers no evidence of such.
Similarly, WO 2012/059232 discloses carbazole and carboline derivatives, and preparation and therapeutic applications thereof. The compounds reportedly are useful against proliferative diseases and parasitic diseases. The authors present evidence that some compounds disclosed inhibit tubulin polymerization for possible application against proliferative diseases but no evidence is presented for activity against trematodes.
The resistance to triclabendazole and lack of effective substitutes creates a pressing need in the field for alternatives that exhibit low side effects and that do not contaminate the animals as a food source. Optimal compositions should further be efficacious, have a quick onset of activity, have a long duration of activity, and be safe to the animal recipients and their human owners.